WO2017017615A1 - Novel dual delayed release oral composition of dexlansoprazole - Google Patents

Novel dual delayed release oral composition of dexlansoprazole Download PDF

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Publication number
WO2017017615A1
WO2017017615A1 PCT/IB2016/054467 IB2016054467W WO2017017615A1 WO 2017017615 A1 WO2017017615 A1 WO 2017017615A1 IB 2016054467 W IB2016054467 W IB 2016054467W WO 2017017615 A1 WO2017017615 A1 WO 2017017615A1
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WIPO (PCT)
Prior art keywords
release
dexlansoprazole
phthalate
pharmaceutical composition
cellulose
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PCT/IB2016/054467
Other languages
French (fr)
Inventor
Anwar Siraj DAUD
Shamsuddin JAMALUDDIN
Original Assignee
Zim Laboratories Ltd.
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Application filed by Zim Laboratories Ltd. filed Critical Zim Laboratories Ltd.
Priority to BR112018001539A priority Critical patent/BR112018001539A2/en
Priority to EP16829940.2A priority patent/EP3328364A4/en
Publication of WO2017017615A1 publication Critical patent/WO2017017615A1/en
Priority to CONC2018/0002046A priority patent/CO2018002046A2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core

Definitions

  • the present disclosure pertains to technical field of pharmaceutical formulation.
  • the present disclosure pertains to novel dual delayed release oral composition of dexlansoprazole or pharmaceutically acceptable salts or hydrated forms thereof, and method of preparation of the same.
  • Dexlansoprazole is a proton pump inhibitor (PPI) that inhibits gastric acid secretion.
  • Chemically Dexlansoprazole is (+)-2-[(R)- ⁇ [3-methyl-4-(2,2,2-trifluoroethoxy) pyridin-2-yl] methyl ⁇ sulfinyl]-lH-benzimidazole.
  • the molecular weight of Dexlansoprazole is about 369.36 and its molecular formula is C16H14F3N302S.
  • Dexlansoprazole is the R-enantiomer of lansoprazole and is represented by compound of structural formu
  • Lansoprazole is described in U. S. Patent No. 4,628,098.
  • the proprietary name of Dexlansoprazole delayed release oral capsule is "DEXILANT" which is marketed by Takeda Pharms in USA.
  • Dexlansoprazole is available as delayed release oral capsule form in 30 mg and 60 mg strengths which was approved on January 30, 2009 to Takeda Pharms, USA. Dexlansoprazole is indicated for healing of all grades of erosive esophagitis (EE), maintaining healing of EE and relief of heartburn and to treating heartburn associated with symptomatic non-erosive gastro esophageal reflux disease (GERD).
  • EE erosive esophagitis
  • GERD gastro esophageal reflux disease
  • Indian Patent Application No. 820/CHE/2009 discloses pharmaceutical compositions comprising a core containing at least one PPI and a coating of modified semi-permeable membrane, which loses its semi-permeable characteristics on exposure to aqueous environment irrespective to the change in pH and allows the drug passage across the coating by diffusion, though maintaining the physical integrity of coating.
  • U.S. Patent No. 8,753,682 discloses the dual release oral tablet of Dexlansoprazole or pharmaceutically acceptable salts or hydrated forms thereof comprising 1) 20% by weight of the Dexlansoprazole in powder form; 2) 80% by weight of the Dexlansoprazole in granule form, wherein the granule form is of different particle size than the powder form; and 3) a single enteric coating that dissolves at between pH 5.5 and 6.4, wherein, upon oral administration, the tablet achieves dual release of the Dexlansoprazole in the small intestine at pH 5.5 and then at pH 6.5, with prevention of dose dumping of the Dexlansoprazole.
  • U.S. Patent No. 8,758,818 discloses dual release oral tablet of Dexlansoprazole comprises Dexlansoprazole in two forms a) powder form and b) granule form and a single enteric coating that dissolves at between pH 5.5 and 6.4, wherein upon oral administration, the tablet achieves dual release of the Dexlansoprazole in that the Dexlansoprazole is released in the small intestine at pH 5.5, and then at pH 6.0 to 6.5, with prevention of dose dumping of the Dexlansoprazole.
  • a first layer comprising: (I) granules, wherein individual granules comprise a core comprising Dexlansoprazole or pharmaceutically acceptable salts or hydrated forms thereof and one or more pharmaceutically acceptable excipients wherein the core is coated with a film, and wherein the film-coated core is coated with an enteric coating that dissolves at pH 5.5 or higher, wherein the enteric coating in the first layer comprises at least one substance selected from cellulose acetate phthalate, cellulose acetate succinate, hydroxpropyl cellulose phthalate, hydroxpropyl ethylcellulose phthalate, hydroxyl propyl methyl cellulose phthalate, hydroxyl propyl methyl cellulose acetate succinate, hydroxyethyl cellulose phthalate, methylcellulose phthalate, polyvinyl acetate phthalate, polyvinylacetate hydrogen phthalate, amylase acetate phthalate, cellulose ester phthalates, cellulose ether phthalates
  • a second layer comprising film-coated granules comprising Dexlansoprazole or pharmaceutically acceptable salts or hydrated forms thereof and one or more pharmaceutically acceptable excipients; wherein the rate controlling agent is in only the first layer and not in the second layer or an optional enteric coating of the entire tablet.
  • U.S. Patent No. 7,790,755 discloses controlled release preparation, in particular a capsule comprising composition (i) comprising a tablet, granule or fine granule wherein the release of active ingredient is controlled; said tablet, granule or fine granule comprising a core particle containing active ingredient and a pH- dependently soluble release-controlled coating-layer which comprises one kind of polymeric substance or a mixture of two or more kinds of polymeric substances having different release properties selected from the group consisting of hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, carboxymethylethyl cellulose, methyl methacrylate-methacrylic acid copolymer(s), methacrylic acid-ethyl acrylate copolymer(s), methacrylic acid-methyl acrylate -methyl methacrylate copolymer(s), hydroxypropyl cellulose acetate succinate, polyvinyl acetate phthalate
  • US'755 further teaches that the active ingredient present in the controlled release preparation is selected from Lansoprazole, an optically active R-isomer of Lansoprazole (Dexlansoprazole) or an optically active S- isomer of Lansoprazole.
  • US'755 claimed dual pulse composition which is based upon the pH-dependently soluble release-controlled coating -layer that releases the active ingredient in dual pulse i.e. (i) first pulse releases the active ingredient at pH range of no less than 5.0, nor more than 6.0 and (ii) second pulse releases the active ingredient at pH range of 6.0 to 7.5.
  • US'755 teaches that a further extension of sustainability becomes possible by combining coating based pH-dependently soluble release-controlled system with a control of migration speed in the gastrointestinal tract.
  • the pH dependent polymer(s) may vary its solubilisation in inter-patient variability or in intra-patient at different physiological conditions in different stages of disease which leads to poor site-specificity of the formulations.
  • the numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term "about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some embodiments of the invention may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
  • aspects of the present disclosure relates to modified release oral pharmaceutical composition of dexlansoprazole or pharmaceutically acceptable salts or hydrated forms thereof having a desired drug release profile.
  • the present disclosure provides a dual delayed release oral pharmaceutical composition of dexlansoprazole or pharmaceutically acceptable salts or hydrated forms thereof that can incorporate two pulsatile release formulations (a) and (b).
  • formulation (a) can include: (i) a core particle comprising dexlansoprazole or a pharmaceutically acceptable salt or a hydrate thereof, and (ii) a pH-dependent release-controlled layer; and formulation (b) can include: (i) a core particle comprising dexlansoprazole or a pharmaceutically acceptable salt or a hydrate thereof, (ii) a pH-independent release-controlled layer, and (iii) a pH-dependent release-controlled layer.
  • the modified release oral pharmaceutical composition can release the active ingredient in two pulses i.e. a first pulse of the active ingredient upon administration of the composition to an individual and a second pulse following entry of the composition into the higher pH environment of the intestines.
  • the two pulsatile release formulations of dexlansoprazole may be in the form of pellets, tablets, granules or fine granules.
  • the core particle can be in the form of an active core particle made of dexlansoprazole or a pharmaceutically acceptable salt or a hydrate thereof.
  • the core particle may be an inert core particle coated with a layer of dexlansoprazole or a pharmaceutically acceptable salt or a hydrate thereof.
  • the core particles can further incorporate a basic inorganic salt stabilizer, one or more gel-forming polymers and one or more pharmaceutically acceptable excipients.
  • the pH-independent release-controlled layer can be formed of a hydrophilic polymer that can be selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), carboxyvinyl polymer, polyethylene glycol 6000, lactose, mannitol, pullulan, agar, gellan gum, guar gum, carageenan, acacia gum, gum arabic, dextran, pectin and mixtures thereof.
  • HPMC hydroxypropyl methylcellulose
  • HPC hydroxypropylcellulose
  • PVP polyvinylpyrrolidone
  • carboxyvinyl polymer polyethylene glycol 6000
  • lactose lactose
  • mannitol pullulan
  • pullulan agar
  • gellan gum gellan gum
  • guar gum carageenan
  • acacia gum gum arabic
  • dextran dextran
  • the pH-independent release-controlled layer can be formed of a hydrophobic polymer that can be selected from the group consisting of ethyl cellulose, Eudragit® RL, Eudragit® RS, hydrogenated vegetable oils, glyceryl behenate, wax, fatty acid, fatty alcohol, shellac and mixtures thereof.
  • the pH-dependent release-controlled layer can be formed of an enteric coating polymer that can be selected from the group consisting of cellulose acetate trimellitate, methacrylic acid, methyl methacrylate copolymer, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl cellulose phthalate, hydroxypropyl ethyl cellulose phthalate, hydroxyl propyl methyl cellulose phthalate, hydroxyl propyl methyl cellulose acetate succinate, hydroxyethyl cellulose phthalate, methylcellulose phthalate, polyvinyl acetate phthalate, polyvinyl acetate hydrogen phthalate, amylase acetate phthalate, cellulose ester phthalates, cellulose ether phthalates, sodium cellulose acetate phthalate, starch acid phthalate, cellulose acetate butyrate, cellulose acetate maleate, cellulose acetate propionate, styrene maleic
  • the pH-dependent release-controlled layer of formulation (a) can dissolve at a pH ranging from 4.5 to 6 to release a first pulse of the active ingredient.
  • the pH-independent soluble release-controlled layer of formulation (b) can dissolve at higher pH levels, for example pH of 6 or above, to release a second pulse of the active ingredient after the first pulse.
  • release of second pulse of active ingredient from the formulation (b) can be time dependent, and the release can further depend upon rate of erosion, diffusion, solubility and/or permeability of the pH-independent layer to intestinal fluids.
  • FIG. 1 shows cross section of one preferred embodiment of formulation (a-1) formulated in accordance with embodiments of the present disclosure.
  • FIG. 2 shows cross section of one preferred embodiment of formulation (b-1) formulated in accordance with embodiments of the present disclosure.
  • the numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term "about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable.
  • aspects of the present disclosure relates to modified release oral pharmaceutical composition of dexlansoprazole or pharmaceutically acceptable salts or hydrated forms thereof having a desired drug release profile.
  • the present disclosure provides a dual delayed release pharmaceutical composition of dexlansoprazole or pharmaceutically acceptable salts or hydrated forms thereof.
  • the dual delayed release pharmaceutical composition can incorporate two pulsatile release formulations (a) and (b), wherein formulation (a) can include: (i) a core particle comprising dexlansoprazole or a pharmaceutically acceptable salt or a hydrate thereof, and (ii) a pH-dependent release-controlled layer; and formulation (b) can include: (i) a core particle comprising dexlansoprazole or a pharmaceutically acceptable salt or a hydrate thereof, (ii) a pH-independent release -controlled layer, and (iii) a pH-dependent release-controlled layer.
  • distallansoprazole includes the compound dexlansoprazole and its pharmaceutically acceptable salts, polymorphs, solvates and hydrates.
  • delayed release refers to release of dexlansoprazole from an oral pharmaceutical composition, in which dexlansoprazole is released over an extended period of time and/or at a particular location and is taken to encompass prolonged release, timed release, controlled release, retarded release, extended release and sustained release.
  • the core particle can be in the form of an active core particle made of dexlansoprazole or a pharmaceutically acceptable salt or a hydrate thereof.
  • the core particle may be an inert core particle coated with a layer of dexlansoprazole or a pharmaceutically acceptable salt or a hydrate thereof.
  • dexlansoprazole may be mixed with an alkaline compound and one or more pharmaceutically acceptable excipients, and the resulting mixture can be formed into an active core.
  • Said active core particles may be produced by extrusion/spheronization, balling or compression utilizing appropriate process equipments. Thus manufactured core materials may be optionally layered with additional pharmaceutical ingredient(s) and active substance(s), and be used for further processing.
  • dexlansoprazole may be mixed with an alkaline compound and one or more pharmaceutically acceptable excipients, and the resulting mixture can be coated on inert seeds to produce core particles.
  • the inert seeds which can be layered with the active substance can include, but not limited to, water insoluble seeds comprising different oxides, celluloses, organic polymers, and water soluble seeds comprising different inorganic salts, sugars, non-pareils.
  • the term "pharmaceutically acceptable excipients” can include, but not limited to, binders, diluents, fillers, disintegrants, basic stabilizers, pore forming substances, gel forming polymers, lubricants, glidants, plasticizers, opacifiers, colouring agents, flavoring agents, solvents and mixtures thereof.
  • Suitable binders can include, but not limited to, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, polyvinyl alcohol, Poly vinyl pyrrolidone (PVP), Macrogol, Pullronic F68, gum arabic, polymethacrylates, gelatin, starch and mixtures thereof.
  • HPMC hydroxypropyl methylcellulose
  • PVP Poly vinyl pyrrolidone
  • Macrogol Poly vinyl pyrrolidone
  • Pullronic F68 gum arabic
  • gelatin starch and mixtures thereof.
  • Suitable diluents or fillers can include, but not limited to, microcrystalline cellulose, cellulose, lactose, starch, calcium phosphates, calcium sulphates, mannitol, glucose, sucrose, sorbitol and mixtures thereof.
  • Suitable disintegrants can include, but not limited to, crosslinked carboxymetyl cellulose, sodium starch glycolate, alginic acid and salts, sodium carboxymethyl cellulose, starch, crosslinked polyvinyl pyrrolidone and mixtures thereof.
  • suitable basic stabilizers can include, but not limited to, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, magnesium oxide, calcium oxide, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium phosphate, magnesium silicate, magnesium aluminate, magnesium metasilicate aluminate, synthetic hydrotalcite, aluminum hydroxide -magnesium, meglumine, lysine, ethylenediamine, ⁇ , ⁇ '-dibenzyl ethylenediamine, procaine, chloroprocaine, choline, diethanolamine and mixtures thereof.
  • suitable pore forming substances can include, but not limited to, mannitol, dextrose, sucrose, lactose, HPMC, HPC, carboxyvinyl polymer, polyethylene glycol 6000, mannitol, an organic acid and mixtures thereof.
  • Suitable gel forming polymers can include, but not limited to, polyethylene oxide (PEO), hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC-Na), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose and carboxyvinyl polymer and mixtures thereof.
  • suitable lubricants can include, but not limited to, stearic acid, magnesium, magnesium stearate, calcium or sodium stearate, sodium stearyl fumarate, talc, waxes e.g. carnauba wax, liquid paraffin, glyceryl monostearates, palmitic acid, sodium or magnesium lauryl sulfate, calcium soaps, zinc stearate, polyethylene glycol, sucrose fatty acid ester, polyoxyethylene monostearates, calcium silicate, silicon dioxide, hydrogenated vegetable oils and fats and mixtures thereof.
  • stearic acid e.g. carnauba wax, liquid paraffin, glyceryl monostearates, palmitic acid, sodium or magnesium lauryl sulfate, calcium soaps, zinc stearate, polyethylene glycol, sucrose fatty acid ester, polyoxyethylene monostearates, calcium silicate, silicon dioxide, hydrogenated vegetable oils and fats and mixtures thereof.
  • Suitable glidants can include, but not limited to, talc, aluminium silicate, colloidal silicon dioxide, starch and mixtures thereof.
  • plasticizers can include, but not limited to, polyethylene glycol, dibutyl sebacate, diethyl phthalate, dibutyl phthalate, triacetin, triethyl citrate, acetylated monoglyceride, castor oil and mixtures thereof.
  • Suitable opacifiers can include, but not limited to, titanium dioxide, iron oxide, zinc oxide, and mixtures thereof.
  • suitable colouring agents can include, but not limited to, Food, Drug & Cosmetic (FD&C) dyes such as FD&C blue, FD&C green, FD&C red, FD&C yellow and FD&C lakes; indigo Drug & Cosmetic (D&C) blue, indigotine FD&C blue, carmoisine indigotine (indigo Carmine); iron oxides such as iron oxide red, yellow, black; quinoline yellow, flaming red, carmine, carmoisine, sunset yellow and mixtures thereof.
  • FD&C Food, Drug & Cosmetic
  • D&C indigo Drug & Cosmetic
  • D&C indigotine FD&C blue
  • carmoisine indigotine indigotine
  • iron oxides such as iron oxide red, yellow, black
  • quinoline yellow quinoline yellow, flaming red, carmine, carmoisine, sunset yellow and mixtures thereof.
  • flavouring agents can include, but not limited to, menthol, peppermint, cinnamon, chocolate, vanillin or fruit essences such as cherry, orange, strawberry, grape, black currant, raspberry, banana, red fruits, wild berries and mixtures thereof.
  • the pH-independent release-controlled layer can be formed of a hydrophilic polymer that can be selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), carboxyvinyl polymer, polyethylene glycol 6000, lactose, mannitol, pullulan, agar, gellan gum, guar gum, carageenan, acacia gum, gum arabic, dextran, pectin and mixtures thereof.
  • HPMC hydroxypropyl methylcellulose
  • HPC hydroxypropylcellulose
  • the pH-independent release-controlled layer can be formed of a hydrophobic polymer that can be selected from the group consisting of ethyl cellulose, Eudragit® RL, Eudragit® RS, hydrogenated vegetable oils, glyceryl behenate, wax, fatty acid, fatty alcohol, shellac and mixtures thereof.
  • the pH-dependent release-controlled layer can be formed of an enteric coating polymer that can be selected from the group consisting of cellulose acetate trimellitate, methacrylic acid, methyl methacrylate copolymer, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl cellulose phthalate, hydroxypropyl ethyl cellulose phthalate, hydroxyl propyl methyl cellulose phthalate, hydroxyl propyl methyl cellulose acetate succinate, hydroxyethyl cellulose phthalate, methylcellulose phthalate, polyvinyl acetate phthalate, polyvinyl acetate hydrogen phthalate, amylase acetate phthalate, cellulose ester phthalates, cellulose ether phthalates, sodium cellulose acetate phthalate, starch acid phthalate, cellulose acetate butyrate, cellulose acetate maleate, cellulose acetate propionate, styrene maleic
  • the two pulsatile release formulations (a) and (b) can be formulated in the form of pellets, tablets, granules, or fine granules, most preferably in the form of pellets.
  • the dual delayed release pharmaceutical composition of dexlansoprazole can be produced in the form of tablet or capsule.
  • the two pulsatile release formulations (a) and (b) can be produced in the form of pellets, which in turn can be filled into a capsule.
  • the pellets can be mixed with one or more excipients and compressed into a multiple unit tablet dosage form.
  • the present disclosure provides a dual delayed release oral pharmaceutical composition of dexlansoprazole, wherein the composition can include: formulation (a-1) comprising a pellet, a tablet, a granule, or a fine granule in which release of dexlansoprazole is controlled; wherein the pellet, tablet, granule, or the fine granule comprising:
  • a core particle comprising dexlansoprazole or a pharmaceutically acceptable salt or a hydrate thereof;
  • formulation (b-1) comprising a pellet, a tablet, a granule, or a fine granule in which release of dexlansoprazole is controlled; wherein the pellet, tablet, granule, or the fine granule comprising:
  • a core particle comprising dexlansoprazole or a pharmaceutically acceptable salt or a hydrate thereof;
  • the core particle of formulation (a-1) and (b-1) may be coated with a seal coat prior to the application of the delayed release coating.
  • the seal coat layer may be produced using one or more film forming polymers including, but not limited to, hydroxypropyl methylcellulose, hydroxypropyl cellulose, lowsubstituted hydroxypropyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, methyl and ethyl cellulose, PVP/vinyl acetate copolymers, PV A/PEG copolymers and alike.
  • FIG. 1 shows cross section of formulation (a-1) formulated in accordance with embodiments of the present disclosure.
  • Formulation (a-1) can include an inner inert seed that can be coated with a drug layer.
  • the drug layer can include dexlansoprazole and one or more pharmaceutically acceptable excipients.
  • a seal coat layer can be coated on the drug layer before application of the delayed release coating.
  • a pH- dependent release-controlled layer can then be coated on the seal coat layer to provide formulation (a-1) in the form of pellets, tablets, granules, or fine granules.
  • formulation (b-1) can include an inner inert seed, a drug layer surrounding the inert seed, a seal coat layer surrounding the drug layer, a pH-independent release-controlled layer on the seal coat layer and a pH-dependent release-controlled layer.
  • the pH-dependent release-controlled layer of formulation (a-1) can dissolve at a pH ranging from 4.5 to 6 to release a first pulse of the active ingredient.
  • the pH-independent release-controlled layer of formulation (b-1) can dissolve at higher pH levels, for example a pH of 6 or above, to release a second pulse of the active ingredient after the first pulse.
  • release of second pulse of active ingredient from the formulation (b-1) can be time dependent, and the release can further depend upon rate of erosion, diffusion, solubility and/or permeability of the pH-independent release-controlled layer to intestinal fluids.
  • the pH-dependent release-controlled layer of formulation (a-1) and (b-1) can be soluble at a pH ranging from 4.5 to 6, preferably at a pH of 5.5.
  • the modified release oral pharmaceutical composition can release the active ingredient in two pulses i.e. a first pulse of the active ingredient upon administration of the composition to an individual and a second pulse following entry of the composition into the higher pH environment of the intestines.
  • Step IV Enteric coating (Part IB)
  • Step VI Pellets Filling
  • part I and Part II pellets For filling into capsule mix both part I and Part II pellets. Fill into empty shell 150mg pellets for 30mg dose and 300mg pellets for 60mg dose.
  • Step IV Enteric coating (Part IB)
  • Step VI Pellets Filling
  • part I and Part II pellets For filling into capsule mix both part I and Part II pellets. Fill into empty shell 150mg pellets for 30mg dose and 300mg pellets for 60mg dose.
  • Step IV Enteric coating (Part IB) a) Coat enteric coated pellets from stage III with following solution.
  • Step VI Pellets Filling
  • part I and Part II pellets For filling into capsule mix both part I and Part II pellets. Fill into empty shell 150mg pellets for 30mg dose and 300mg pellets for 60mg dose.
  • Step IV Enteric coating (Part IB)
  • Step VI Pellets Filling
  • part I and Part II pellets For filling into capsule mix both part I and Part II pellets. Fill into empty shell 150mg pellets for 30mg dose and 300mg pellets for 60mg dose.

Abstract

The present disclosure provides a dual delayed release oral pharmaceutical composition of dexlansoprazole or pharmaceutically acceptable salts or hydrated forms thereof. The disclosed dual delayed release pharmaceutical composition can incorporate two pulsatile release formulations (a) and (b), wherein formulation (a) can include: (i) a core particle comprising dexlansoprazole or a pharmaceutically acceptable salt or a hydrate thereof, and (ii) a p H-dependent release-controlled layer; and formulation (b) can include: (i) a core particle comprising dexlansoprazole or a pharmaceutically acceptable salt or a hydrate thereof, (ii) a p H-independent release-controlled layer, and (iii) a p H-dependent release-controlled layer.

Description

NOVEL DUAL DELAYED RELEASE ORAL COMPOSITION OF
DEXLANSOPRAZOLE
FIELD OF THE INVENTION
[0001] The present disclosure pertains to technical field of pharmaceutical formulation. In particular, the present disclosure pertains to novel dual delayed release oral composition of dexlansoprazole or pharmaceutically acceptable salts or hydrated forms thereof, and method of preparation of the same.
BACKGROUND OF THE INVENTION
[0002] The background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
[0003] Dexlansoprazole is a proton pump inhibitor (PPI) that inhibits gastric acid secretion. Chemically Dexlansoprazole is (+)-2-[(R)-{[3-methyl-4-(2,2,2-trifluoroethoxy) pyridin-2-yl] methyl} sulfinyl]-lH-benzimidazole. The molecular weight of Dexlansoprazole is about 369.36 and its molecular formula is C16H14F3N302S. Dexlansoprazole is the R-enantiomer of lansoprazole and is represented by compound of structural formu
Figure imgf000002_0001
Formula I
Lansoprazole is described in U. S. Patent No. 4,628,098. The proprietary name of Dexlansoprazole delayed release oral capsule is "DEXILANT" which is marketed by Takeda Pharms in USA.
[0004] Dexlansoprazole is available as delayed release oral capsule form in 30 mg and 60 mg strengths which was approved on January 30, 2009 to Takeda Pharms, USA. Dexlansoprazole is indicated for healing of all grades of erosive esophagitis (EE), maintaining healing of EE and relief of heartburn and to treating heartburn associated with symptomatic non-erosive gastro esophageal reflux disease (GERD).
[0005] Indian Patent Application No. 820/CHE/2009 discloses pharmaceutical compositions comprising a core containing at least one PPI and a coating of modified semi-permeable membrane, which loses its semi-permeable characteristics on exposure to aqueous environment irrespective to the change in pH and allows the drug passage across the coating by diffusion, though maintaining the physical integrity of coating.
[0006] U.S. Patent No. 8,753,682 discloses the dual release oral tablet of Dexlansoprazole or pharmaceutically acceptable salts or hydrated forms thereof comprising 1) 20% by weight of the Dexlansoprazole in powder form; 2) 80% by weight of the Dexlansoprazole in granule form, wherein the granule form is of different particle size than the powder form; and 3) a single enteric coating that dissolves at between pH 5.5 and 6.4, wherein, upon oral administration, the tablet achieves dual release of the Dexlansoprazole in the small intestine at pH 5.5 and then at pH 6.5, with prevention of dose dumping of the Dexlansoprazole.
[0007] U.S. Patent No. 8,758,818 discloses dual release oral tablet of Dexlansoprazole comprises Dexlansoprazole in two forms a) powder form and b) granule form and a single enteric coating that dissolves at between pH 5.5 and 6.4, wherein upon oral administration, the tablet achieves dual release of the Dexlansoprazole in that the Dexlansoprazole is released in the small intestine at pH 5.5, and then at pH 6.0 to 6.5, with prevention of dose dumping of the Dexlansoprazole.
[0008] Chinese (CN) Patent application No. 04940169 discloses Dexlansoprazole sustained release capsule provided Dexlansoprazole is hardly released in gastric acid, and disintegrated in intestines, and active ingredients are dissolved out, so that destruction of Dexlansoprazole in the gastric acid is avoided; the Dexlansoprazole sustained release capsule contains two different types of enteric micro pellets, so that two-time dual drug release (DDR) is realized; it mainly used EUDRAGIT S 100 and in a process of preparing EUDRAGIT S 100 aqueous dispersion, different amounts of alkaline substances are added, different mol numbers of carboxyls in polymers are neutralized, and an enteric- coating material is controlled to be dissolved at different pH values, so that two-time release is realized; besides, an aqueous dispersion coating is adopted, so that ethanol residue is effectively avoided. [0009] U.S. Patent No. 9, 114,085 discloses modified release bilayer tablet comprising
(a) a first layer comprising: (I) granules, wherein individual granules comprise a core comprising Dexlansoprazole or pharmaceutically acceptable salts or hydrated forms thereof and one or more pharmaceutically acceptable excipients wherein the core is coated with a film, and wherein the film-coated core is coated with an enteric coating that dissolves at pH 5.5 or higher, wherein the enteric coating in the first layer comprises at least one substance selected from cellulose acetate phthalate, cellulose acetate succinate, hydroxpropyl cellulose phthalate, hydroxpropyl ethylcellulose phthalate, hydroxyl propyl methyl cellulose phthalate, hydroxyl propyl methyl cellulose acetate succinate, hydroxyethyl cellulose phthalate, methylcellulose phthalate, polyvinyl acetate phthalate, polyvinylacetate hydrogen phthalate, amylase acetate phthalate, cellulose ester phthalates, cellulose ether phthalates, sodium cellulose acetate phthalate, starch acid phthalate, cellulose acetate butyrate, cellulose acetate maleate, cellulose acetate trimellitate, cellulose acetate propionate, styrene maleic acid dibutyl phthalate copolymer(s), styrene maleic acid polyvinyl acetate phthalate copolymer(s) propionate, shellac, and mixtures thereof; and (II) a rate controlling agent that dissolves independently from pH; and
(b) a second layer comprising film-coated granules comprising Dexlansoprazole or pharmaceutically acceptable salts or hydrated forms thereof and one or more pharmaceutically acceptable excipients; wherein the rate controlling agent is in only the first layer and not in the second layer or an optional enteric coating of the entire tablet.
[0010] U.S. Patent No. 7,790,755 (hereinafter US'755) discloses controlled release preparation, in particular a capsule comprising composition (i) comprising a tablet, granule or fine granule wherein the release of active ingredient is controlled; said tablet, granule or fine granule comprising a core particle containing active ingredient and a pH- dependently soluble release-controlled coating-layer which comprises one kind of polymeric substance or a mixture of two or more kinds of polymeric substances having different release properties selected from the group consisting of hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, carboxymethylethyl cellulose, methyl methacrylate-methacrylic acid copolymer(s), methacrylic acid-ethyl acrylate copolymer(s), methacrylic acid-methyl acrylate -methyl methacrylate copolymer(s), hydroxypropyl cellulose acetate succinate, polyvinyl acetate phthalate and shellac; said polymeric substance is soluble in the pH range of 6.0 to 7.5, and composition (ii) comprising a tablet, granule or fine granule comprising a core particle containing the active ingredient and enteric coat such that the active ingredient is released in the pH range of no less than 5.0 to no more than 6.0. US'755 further teaches that the active ingredient present in the controlled release preparation is selected from Lansoprazole, an optically active R-isomer of Lansoprazole (Dexlansoprazole) or an optically active S- isomer of Lansoprazole. US'755 claimed dual pulse composition which is based upon the pH-dependently soluble release-controlled coating -layer that releases the active ingredient in dual pulse i.e. (i) first pulse releases the active ingredient at pH range of no less than 5.0, nor more than 6.0 and (ii) second pulse releases the active ingredient at pH range of 6.0 to 7.5.
[0011] US'755 teaches that a further extension of sustainability becomes possible by combining coating based pH-dependently soluble release-controlled system with a control of migration speed in the gastrointestinal tract. However, the pH dependent polymer(s) may vary its solubilisation in inter-patient variability or in intra-patient at different physiological conditions in different stages of disease which leads to poor site-specificity of the formulations.
[0012] Accordingly, there exists a need in the art for a new and improved modified release oral pharmaceutical composition of dexlansoprazole that satisfies the existing needs and overcomes the deficiencies found in the prior art. Further, it would be advantageous to provide a dual delayed release oral composition for complete and rapid release of dexlansoprazole after a lag time so as to match body's circadian rhythms with the release of the drug which increases the efficacy and safety of the drug by proportioning its peak plasma concentration during the 24 hours in synchrony with biological rhythm for the treatment of esophagitis, gastritis, duodenitis, gastric ulcers and duodenal ulcers.
[0013] All publications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.
[0014] In some embodiments, the numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term "about." Accordingly, in some embodiments, the numerical parameters set forth in the written description are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some embodiments of the invention may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
[0015] As used in the description herein and throughout the claims that follow, the meaning of "a," "an," and "the" includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein, the meaning of "in" includes "in" and "on" unless the context clearly dictates otherwise.
[0016] The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. "such as") provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed.
[0017] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience and/or patentability.
OBJECTS OF THE INVENTION
[0018] It is an object of the present disclosure to provide an improved modified release oral pharmaceutical composition of dexlansoprazole that overcomes one or more disadvantages associated with previously known dexlansoprazole compositions. [0019] It is a further object of the present disclosure to provide a new and improved modified release oral pharmaceutical composition of dexlansoprazole that exhibits desired drug release profile.
[0020] It is another object of the present disclosure to provide a new and improved modified release oral pharmaceutical composition of dexlansoprazole that sustains pharmacological effect of dexlansoprazole for a prolonged period of time to have a desired release profile.
[0021] It is another object of the present disclosure to provide a process for preparing modified release oral pharmaceutical composition of dexlansoprazole having a desired drug release profile.
SUMMARY OF THE INVENTION
[0022] Aspects of the present disclosure relates to modified release oral pharmaceutical composition of dexlansoprazole or pharmaceutically acceptable salts or hydrated forms thereof having a desired drug release profile. In an aspect, the present disclosure provides a dual delayed release oral pharmaceutical composition of dexlansoprazole or pharmaceutically acceptable salts or hydrated forms thereof that can incorporate two pulsatile release formulations (a) and (b).
[0023] According to embodiments of the present disclosure, formulation (a) can include: (i) a core particle comprising dexlansoprazole or a pharmaceutically acceptable salt or a hydrate thereof, and (ii) a pH-dependent release-controlled layer; and formulation (b) can include: (i) a core particle comprising dexlansoprazole or a pharmaceutically acceptable salt or a hydrate thereof, (ii) a pH-independent release-controlled layer, and (iii) a pH-dependent release-controlled layer.
[0024] According to embodiments of the present disclosure, the modified release oral pharmaceutical composition can release the active ingredient in two pulses i.e. a first pulse of the active ingredient upon administration of the composition to an individual and a second pulse following entry of the composition into the higher pH environment of the intestines.
[0025] In an embodiment, the two pulsatile release formulations of dexlansoprazole may be in the form of pellets, tablets, granules or fine granules.
[0026] In an embodiment, the core particle can be in the form of an active core particle made of dexlansoprazole or a pharmaceutically acceptable salt or a hydrate thereof. In an alternative embodiment, the core particle may be an inert core particle coated with a layer of dexlansoprazole or a pharmaceutically acceptable salt or a hydrate thereof.
[0027] In an embodiment, the core particles can further incorporate a basic inorganic salt stabilizer, one or more gel-forming polymers and one or more pharmaceutically acceptable excipients.
[0028] In an embodiment, the pH-independent release-controlled layer can be formed of a hydrophilic polymer that can be selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), carboxyvinyl polymer, polyethylene glycol 6000, lactose, mannitol, pullulan, agar, gellan gum, guar gum, carageenan, acacia gum, gum arabic, dextran, pectin and mixtures thereof.
[0029] In another embodiment, the pH-independent release-controlled layer can be formed of a hydrophobic polymer that can be selected from the group consisting of ethyl cellulose, Eudragit® RL, Eudragit® RS, hydrogenated vegetable oils, glyceryl behenate, wax, fatty acid, fatty alcohol, shellac and mixtures thereof.
[0030] In an embodiment, the pH-dependent release-controlled layer can be formed of an enteric coating polymer that can be selected from the group consisting of cellulose acetate trimellitate, methacrylic acid, methyl methacrylate copolymer, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl cellulose phthalate, hydroxypropyl ethyl cellulose phthalate, hydroxyl propyl methyl cellulose phthalate, hydroxyl propyl methyl cellulose acetate succinate, hydroxyethyl cellulose phthalate, methylcellulose phthalate, polyvinyl acetate phthalate, polyvinyl acetate hydrogen phthalate, amylase acetate phthalate, cellulose ester phthalates, cellulose ether phthalates, sodium cellulose acetate phthalate, starch acid phthalate, cellulose acetate butyrate, cellulose acetate maleate, cellulose acetate propionate, styrene maleic acid dibutyl phthalate copolymer, styrene maleic acid polyvinyl acetate phthalate copolymer propionate, shellac and mixtures thereof.
[0031] In an embodiment, the pH-dependent release-controlled layer of formulation (a) can dissolve at a pH ranging from 4.5 to 6 to release a first pulse of the active ingredient. The pH-independent soluble release-controlled layer of formulation (b) can dissolve at higher pH levels, for example pH of 6 or above, to release a second pulse of the active ingredient after the first pulse. [0032] In an embodiment, release of second pulse of active ingredient from the formulation (b) can be time dependent, and the release can further depend upon rate of erosion, diffusion, solubility and/or permeability of the pH-independent layer to intestinal fluids.
[0033] Various objects, features, aspects and advantages of the inventive subject matter will become more apparent from the following detailed description of preferred embodiments.
BRIEF DESCRIPTION OF THE DRAWINGS
[0034] The accompanying drawings are included to provide a further understanding of the present disclosure, and are incorporated in and constitute a part of this specification.
The drawings illustrate exemplary embodiments of the present disclosure and, together with the description, serve to explain the principles of the present disclosure.
[0035] FIG. 1 shows cross section of one preferred embodiment of formulation (a-1) formulated in accordance with embodiments of the present disclosure.
[0036] FIG. 2 shows cross section of one preferred embodiment of formulation (b-1) formulated in accordance with embodiments of the present disclosure.
DETAILED DESCRIPTION OF THE INVENTION
[0037] The following is a detailed description of embodiments of the disclosure depicted in the accompanying drawings. The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims.
[0038] Unless the context requires otherwise, throughout the specification which follow, the word "comprise" and variations thereof, such as, "comprises" and "comprising" are to be construed in an open, inclusive sense that is as "including, but not limited to."
[0039] Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
[0040] As used in the description herein and throughout the claims that follow, the meaning of "a," "an," and "the" includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein, the meaning of "in" includes "in" and "on" unless the context clearly dictates otherwise.
[0041] In some embodiments, the numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term "about." Accordingly, in some embodiments, the numerical parameters set forth in the written description are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable.
[0042] The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. "such as") provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
[0043] The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.
[0044] All methods described herein can be performed in suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. "such as") provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
[0045] Various terms are used herein. To the extent a term used in a claim is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.
[0046] Aspects of the present disclosure relates to modified release oral pharmaceutical composition of dexlansoprazole or pharmaceutically acceptable salts or hydrated forms thereof having a desired drug release profile.
[0047] In an aspect, the present disclosure provides a dual delayed release pharmaceutical composition of dexlansoprazole or pharmaceutically acceptable salts or hydrated forms thereof. According to embodiments of the present disclosure, the dual delayed release pharmaceutical composition can incorporate two pulsatile release formulations (a) and (b), wherein formulation (a) can include: (i) a core particle comprising dexlansoprazole or a pharmaceutically acceptable salt or a hydrate thereof, and (ii) a pH-dependent release-controlled layer; and formulation (b) can include: (i) a core particle comprising dexlansoprazole or a pharmaceutically acceptable salt or a hydrate thereof, (ii) a pH-independent release -controlled layer, and (iii) a pH-dependent release-controlled layer.
[0048] As used herein, the term "dexlansoprazole" includes the compound dexlansoprazole and its pharmaceutically acceptable salts, polymorphs, solvates and hydrates.
[0049] The term "delayed release" as used herein in refers to release of dexlansoprazole from an oral pharmaceutical composition, in which dexlansoprazole is released over an extended period of time and/or at a particular location and is taken to encompass prolonged release, timed release, controlled release, retarded release, extended release and sustained release.
[0050] In an embodiment, the core particle can be in the form of an active core particle made of dexlansoprazole or a pharmaceutically acceptable salt or a hydrate thereof. In an alternative embodiment, the core particle may be an inert core particle coated with a layer of dexlansoprazole or a pharmaceutically acceptable salt or a hydrate thereof. [0051] In an embodiment, dexlansoprazole may be mixed with an alkaline compound and one or more pharmaceutically acceptable excipients, and the resulting mixture can be formed into an active core. Said active core particles may be produced by extrusion/spheronization, balling or compression utilizing appropriate process equipments. Thus manufactured core materials may be optionally layered with additional pharmaceutical ingredient(s) and active substance(s), and be used for further processing.
[0052] In an alternative embodiment, dexlansoprazole may be mixed with an alkaline compound and one or more pharmaceutically acceptable excipients, and the resulting mixture can be coated on inert seeds to produce core particles. The inert seeds which can be layered with the active substance can include, but not limited to, water insoluble seeds comprising different oxides, celluloses, organic polymers, and water soluble seeds comprising different inorganic salts, sugars, non-pareils.
[0053] As used herein the term "pharmaceutically acceptable excipients" can include, but not limited to, binders, diluents, fillers, disintegrants, basic stabilizers, pore forming substances, gel forming polymers, lubricants, glidants, plasticizers, opacifiers, colouring agents, flavoring agents, solvents and mixtures thereof.
[0054] Examples of suitable binders can include, but not limited to, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, polyvinyl alcohol, Poly vinyl pyrrolidone (PVP), Macrogol, Pullronic F68, gum arabic, polymethacrylates, gelatin, starch and mixtures thereof.
[0055] Examples of suitable diluents or fillers can include, but not limited to, microcrystalline cellulose, cellulose, lactose, starch, calcium phosphates, calcium sulphates, mannitol, glucose, sucrose, sorbitol and mixtures thereof.
[0056] Examples of suitable disintegrants can include, but not limited to, crosslinked carboxymetyl cellulose, sodium starch glycolate, alginic acid and salts, sodium carboxymethyl cellulose, starch, crosslinked polyvinyl pyrrolidone and mixtures thereof.
[0057] Examples of suitable basic stabilizers can include, but not limited to, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, magnesium oxide, calcium oxide, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium phosphate, magnesium silicate, magnesium aluminate, magnesium metasilicate aluminate, synthetic hydrotalcite, aluminum hydroxide -magnesium, meglumine, lysine, ethylenediamine, Ν,Ν'-dibenzyl ethylenediamine, procaine, chloroprocaine, choline, diethanolamine and mixtures thereof.
[0058] Examples of suitable pore forming substances can include, but not limited to, mannitol, dextrose, sucrose, lactose, HPMC, HPC, carboxyvinyl polymer, polyethylene glycol 6000, mannitol, an organic acid and mixtures thereof.
[0059] Examples of suitable gel forming polymers can include, but not limited to, polyethylene oxide (PEO), hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC-Na), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose and carboxyvinyl polymer and mixtures thereof.
[0060] Examples of suitable lubricants can include, but not limited to, stearic acid, magnesium, magnesium stearate, calcium or sodium stearate, sodium stearyl fumarate, talc, waxes e.g. carnauba wax, liquid paraffin, glyceryl monostearates, palmitic acid, sodium or magnesium lauryl sulfate, calcium soaps, zinc stearate, polyethylene glycol, sucrose fatty acid ester, polyoxyethylene monostearates, calcium silicate, silicon dioxide, hydrogenated vegetable oils and fats and mixtures thereof.
[0061] Examples of suitable glidants can include, but not limited to, talc, aluminium silicate, colloidal silicon dioxide, starch and mixtures thereof.
[0062] Examples of suitable plasticizers can include, but not limited to, polyethylene glycol, dibutyl sebacate, diethyl phthalate, dibutyl phthalate, triacetin, triethyl citrate, acetylated monoglyceride, castor oil and mixtures thereof.
[0063] Examples of suitable opacifiers can include, but not limited to, titanium dioxide, iron oxide, zinc oxide, and mixtures thereof.
[0064] Examples of suitable colouring agents can include, but not limited to, Food, Drug & Cosmetic (FD&C) dyes such as FD&C blue, FD&C green, FD&C red, FD&C yellow and FD&C lakes; indigo Drug & Cosmetic (D&C) blue, indigotine FD&C blue, carmoisine indigotine (indigo Carmine); iron oxides such as iron oxide red, yellow, black; quinoline yellow, flaming red, carmine, carmoisine, sunset yellow and mixtures thereof.
[0065] Examples of suitable flavouring agents can include, but not limited to, menthol, peppermint, cinnamon, chocolate, vanillin or fruit essences such as cherry, orange, strawberry, grape, black currant, raspberry, banana, red fruits, wild berries and mixtures thereof.
[0066] Examples of suitable solvents that can be used in the formulation of core particle can include aqueous, non-aqueous solvents and mixtures thereof. [0067] In an embodiment, the pH-independent release-controlled layer can be formed of a hydrophilic polymer that can be selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), carboxyvinyl polymer, polyethylene glycol 6000, lactose, mannitol, pullulan, agar, gellan gum, guar gum, carageenan, acacia gum, gum arabic, dextran, pectin and mixtures thereof.
[0068] In another embodiment, the pH-independent release-controlled layer can be formed of a hydrophobic polymer that can be selected from the group consisting of ethyl cellulose, Eudragit® RL, Eudragit® RS, hydrogenated vegetable oils, glyceryl behenate, wax, fatty acid, fatty alcohol, shellac and mixtures thereof.
[0069] In an embodiment, the pH-dependent release-controlled layer can be formed of an enteric coating polymer that can be selected from the group consisting of cellulose acetate trimellitate, methacrylic acid, methyl methacrylate copolymer, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl cellulose phthalate, hydroxypropyl ethyl cellulose phthalate, hydroxyl propyl methyl cellulose phthalate, hydroxyl propyl methyl cellulose acetate succinate, hydroxyethyl cellulose phthalate, methylcellulose phthalate, polyvinyl acetate phthalate, polyvinyl acetate hydrogen phthalate, amylase acetate phthalate, cellulose ester phthalates, cellulose ether phthalates, sodium cellulose acetate phthalate, starch acid phthalate, cellulose acetate butyrate, cellulose acetate maleate, cellulose acetate propionate, styrene maleic acid dibutyl phthalate copolymer, styrene maleic acid polyvinyl acetate phthalate copolymer propionate, shellac and mixtures thereof.
[0070] In an embodiment, the two pulsatile release formulations (a) and (b) can be formulated in the form of pellets, tablets, granules, or fine granules, most preferably in the form of pellets.
[0071] In an embodiment, the dual delayed release pharmaceutical composition of dexlansoprazole can be produced in the form of tablet or capsule.
[0072] In an exemplary embodiment, the two pulsatile release formulations (a) and (b) can be produced in the form of pellets, which in turn can be filled into a capsule. Alternatively, the pellets can be mixed with one or more excipients and compressed into a multiple unit tablet dosage form.
[0073] In an illustrative embodiment, the present disclosure provides a dual delayed release oral pharmaceutical composition of dexlansoprazole, wherein the composition can include: formulation (a-1) comprising a pellet, a tablet, a granule, or a fine granule in which release of dexlansoprazole is controlled; wherein the pellet, tablet, granule, or the fine granule comprising:
a core particle comprising dexlansoprazole or a pharmaceutically acceptable salt or a hydrate thereof;
a pH-independent release-controlled layer on the core particle; and
a pH-dependent release-controlled layer on the pH-independent release- controlled layer; and,
formulation (b-1) comprising a pellet, a tablet, a granule, or a fine granule in which release of dexlansoprazole is controlled; wherein the pellet, tablet, granule, or the fine granule comprising:
a core particle comprising dexlansoprazole or a pharmaceutically acceptable salt or a hydrate thereof; and
a pH-dependent release-controlled layer on the core particle.
[0074] In a preferred embodiment, the core particle of formulation (a-1) and (b-1) may be coated with a seal coat prior to the application of the delayed release coating. The seal coat layer may be produced using one or more film forming polymers including, but not limited to, hydroxypropyl methylcellulose, hydroxypropyl cellulose, lowsubstituted hydroxypropyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, methyl and ethyl cellulose, PVP/vinyl acetate copolymers, PV A/PEG copolymers and alike.
[0075] FIG. 1 shows cross section of formulation (a-1) formulated in accordance with embodiments of the present disclosure. Formulation (a-1) can include an inner inert seed that can be coated with a drug layer. The drug layer can include dexlansoprazole and one or more pharmaceutically acceptable excipients. As shown in FIG. 1, a seal coat layer can be coated on the drug layer before application of the delayed release coating. A pH- dependent release-controlled layer can then be coated on the seal coat layer to provide formulation (a-1) in the form of pellets, tablets, granules, or fine granules.
[0076] Referring to FIG. 2 that shows cross section of formulation (b-1) formulated in accordance with embodiments of the present disclosure. As shown, formulation (b-1) can include an inner inert seed, a drug layer surrounding the inert seed, a seal coat layer surrounding the drug layer, a pH-independent release-controlled layer on the seal coat layer and a pH-dependent release-controlled layer. [0077] In an embodiment, the pH-dependent release-controlled layer of formulation (a-1) can dissolve at a pH ranging from 4.5 to 6 to release a first pulse of the active ingredient. The pH-independent release-controlled layer of formulation (b-1) can dissolve at higher pH levels, for example a pH of 6 or above, to release a second pulse of the active ingredient after the first pulse.
[0078] In an embodiment, release of second pulse of active ingredient from the formulation (b-1) can be time dependent, and the release can further depend upon rate of erosion, diffusion, solubility and/or permeability of the pH-independent release-controlled layer to intestinal fluids.
[0079] In an embodiment, the pH-dependent release-controlled layer of formulation (a-1) and (b-1) can be soluble at a pH ranging from 4.5 to 6, preferably at a pH of 5.5.
[0080] According to embodiments of the present disclosure, the modified release oral pharmaceutical composition can release the active ingredient in two pulses i.e. a first pulse of the active ingredient upon administration of the composition to an individual and a second pulse following entry of the composition into the higher pH environment of the intestines.
[0081] While the foregoing description discloses various embodiments of the disclosure, other and further embodiments of the invention may be devised without departing from the basic scope of the disclosure. The invention is not limited to the described embodiments, versions or examples, which are included to enable a person having ordinary skill in the art to make and use the invention when combined with information and knowledge available to the person having ordinary skill in the art.
EXAMPLES
[0082] The present disclosure is further explained in the form of following examples. However, it is to be understood that the foregoing examples are merely illustrative and are not to be taken as limitations upon the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications may be made without departing from the scope of the invention.
[0083] Example No. 1
A. Manufacturing formula
Sr. No. Ingredients Quantity (mg/capsule) 60mg 30mg
Stagel. Drug core
1. Sugar Globules 121.5 60.75
2. Dexlansoprazole 60 30
3. Magnesium oxide 15.39 7.695
4. Sucrose 12.24 6.12
5. Sodium Lauryl Sulphate 12 6
6. Purified Water q.s. q.s.
221.13 110.565
Stagell. Seal Coating
7. Drug core pellets from Stage I 221.13 110.565
8. HPMC 5cps 21.63 10.815
9. Mannitol 10.8 5.4
10. Purified Talc 1.2 0.6
11. Titanium Dioxide 1.2 0.6
12. Purified Water q.s. q.s.
255.96 127.98
Stage III. pH independent layer (Part I A)
13. Seal coated pellets from Stage II 185.4 92.7
14. PVP K-30 4.155 2.0775
15. Ethyl Cellulose 2.085 1.0425
16. Purified Talc 3.06 1.53
17. Titanium Dioxide 3.06 1.53
18. Triethyl Citrate 2.52 1.26
19. Isopropyl Alcohol q.s. q.s.
200.28 100.14
Stage IV :- Enteric/ pH dependent coating (Part IB)
20. Enteric coated pellets form stage III 200.28 100.14
21. Cellulose acetate trimellitate 9.24 4.62
22. Purified Talc 3.06 1.53
23. Titanium Dioxide 3.06 1.53 24. Triethyl citrate 2.52 1.26
25. Isopropyl alcohol q.s. q.s.
218.16 109.08
Stage V. Enteric Coating (Part II)
26. Seal coated pellets from stage II 70.56 35.28
27. Cellulose acetate trimellitate 5.1 2.55
28. Purified Talc 2.4 1.2
29. Titanium Dioxide 2.7 1.35
30. Triethyl citrate 1.08 0.54
31. Isopropyl alcohol q.s. q.s
81.84 40.92
Stage VI. Capsule filling
32. Part i 218.16 109.08
33. Part II 81.84 40.92
34. Total fill wt. 300 150
35. Hydroxypropyl methylcellulose capsules
B. Manufacturing procedure
Stage I: Drug core
a) Dissolve sucrose and sodium lauryl sulphate in sufficient water, further disperse in it. Dexlansoprazole and Magnesium oxide. Loading this dispersion over the sugar globules in FBC followed by drying at 50°c for 8 hours in drier.
Stage II: Seal coating
a) Dissolve HPMC 5cps and mannitol in sufficient water, further dispersed talc & titanium dioxide in it.
b) Take drug core pellets from stage I and apply seal coating with above suspension (a). c) Dry the pellets at 50°c in drier.
Stage III: pH independent coating (Part IA)
a) Dissolve PVP K-30, Ethyl cellulose & triethyl citrate in sufficient isopropyl alcohol and dispersed titanium dioxide and talc in it.
b) With suspension prepared in (a), coat seal coated pellets from stage II. c) Dry the pellets at 50°c in drier.
Step IV: Enteric coating (Part IB)
a) Coat enteric coated pellets from stage III with following solution.
b) Dissolve cellulose acetate trimellitate and Triethyl citrate in Isopropyl alcohol sufficient quantity, further dispersed titanium dioxide and talc in it.
c) Dry the pellets at 50°c for in drier.
Stage V: Enteric coating (Part II):
a) Dissolve cellulose acetate trimellitate and Triethyl citrate in sufficient quantity of isopropyl alcohol, further dispersed talc & titanium talc in it.
b) Coat with above (a) suspension to seal coated pellets from stage II.
c) Dry the pellets at 50°c in drier.
Step VI: Pellets Filling
For filling into capsule mix both part I and Part II pellets. Fill into empty shell 150mg pellets for 30mg dose and 300mg pellets for 60mg dose.
[0084] Example No. 2
A. Manufacturing Procedure
Quantity (mg/capsule)
Sr. No. Ingredients
60m g 30mg
Stagel. Drug core
1. Sugar Globules 121.5 60.75
2. Dexlansoprazole 60 30
3. Magnesium oxide 15.39 7.695
4. Sucrose 12.24 6.12
5. Sodium Lauryl Sulphate 12 6
6. Purified Water q.s. q.s.
221.13 110.565
Stagell. Seal Coating
7. Drug core pellets from Stage I 221.13 110.565
8. HPMC 5cps 21.63 10.815
9. Mannitol 10.8 5.4
10. Purified Talc 1.2 0.6
11. Titanium Dioxide 1.2 0.6 12. Purified Water q.s. q.s.
255.96 127.98
Stage III. pH independent coating (Part I A)
13. Seal coated pellets from Stage II 185.4 92.7
14. HPC 6.24 3.12
15. Purified Talc 3.06 1.53
16. Titanium Dioxide 3.06 1.53
17. Triethyl Citrate 2.52 1.26
18. Isopropyl Alcohol q.s. q.s.
200.28 100.14
Stage IV :- Enteric coating (Part IB)
19. Enteric coated pellets form stage III 200.28 100.14
20. Cellulose acetate trimellitate 9.24 4.62
21. Purified Talc 3.06 1.53
22. Titanium Dioxide 3.06 1.53
23. Triethyl citrate 2.52 1.26
24. Isopropyl alcohol q.s. q.s.
218.16 109.08
Stage V. Enteric Coating (Part II)
25. Seal coated pellets from stage II 70.56 35.28
26. Cellulose acetate trimellitate 5.1 2.55
27. Purified Talc 2.4 1.2
28. Titanium Dioxide 2.7 1.35
29. Triethyl citrate 1.08 0.54
30. Isopropyl alcohol q.s. q.s
81.84 40.92
Stage V . Capsule filling
31. Part i 218.16 109.08
32. Part II 81.84 40.92
33. Total fill wt. 300 150
34. Hydroxypropyl methylcellulose capsules B. Manufacturing procedure
Stage I: Drug core
a) Dissolve sucrose and sodium lauryl sulphate in sufficient water, further disperse in it. Dexlansoprazole and Magnesium oxide. Loading this dispersion over the sugar globules in FBC followed by drying at 50°c for 8 hours in drier.
Stage II: Seal coating
a) Dissolve HPMC 5cps and mannitol in sufficient water, further dispersed talc & titanium dioxide in it.
b) Take drug core pellets from stage I and apply seal coating with above suspension (a).
c) Dry the pellets at 50°c in drier.
Stage III: pH independent coating (Part IA)
a) Dissolve HPC & triethyl citrate in sufficient isopropyl alcohol and dispersed titanium dioxide and talc in it.
b) With suspension prepared in (a), coat seal coated pellets from stage II.
c) Dry the pellets at 50°c in drier.
Step IV: Enteric coating (Part IB)
a) Coat enteric coated pellets from stage III with following solution.
b) Dissolve cellulose acetate trimellitate and Triethyl citrate in Isopropyl alcohol sufficient quantity, further dispersed titanium dioxide and talc in it.
c) Dry the pellets at 50°c for in drier.
Stage V: Enteric coating (Part II):
a) Dissolve cellulose acetate trimellitate and Triethyl citrate in sufficient quantity of isopropyl alcohol, further dispersed talc & titanium talc in it.
b) Coat with above (a) suspension to seal coated pellets from stage II.
c) Dry the pellets at 50°c in drier.
Step VI: Pellets Filling
For filling into capsule mix both part I and Part II pellets. Fill into empty shell 150mg pellets for 30mg dose and 300mg pellets for 60mg dose.
[0085] Example No 3
A. Manufacturing formula
Quantity (mg/capsule)
Sr. No. Ingredients
60m g 30mg Stagel. Drug core
1. Sugar Globules 121.5 60.75
2. Dexlansoprazole 60 30
3. Magnesium oxide 15.39 7.695
4. Sucrose 12.24 6.12
5. Sodium Lauryl Sulphate 12 6
6. Purified Water q.s. q.s.
221.13 110.565
Stagell. Seal Coating
7. Drug core pellets from Stage I 221.13 110.565
8. HPMC 5cps 21.63 10.815
9. Mannitol 10.8 5.4
10. Purified Talc 1.2 0.6
11. Titanium Dioxide 1.2 0.6
12. Purified Water q.s. q.s.
255.96 127.98
Stage III. pH independent coating (Part I A)
13. Seal coated pellets from Stage II 185.4 92.7
14. PVP K-30 4.155 2.0775
15. Ethyl Cellulose 2.085 1.0425
16. Purified Talc 3.06 1.53
17. Titanium Dioxide 3.06 1.53
18. Triethyl Citrate 2.52 1.26
19. Isopropyl Alcohol q.s. q.s.
200.28 100.14
Stage IV :- Enteric coating (Part IB)
20. Enteric coated pellets form stage III 200.28 100.14
21. Eudragit L100-55 9.24 4.62
22. Purified Talc 3.06 1.53
23. Titanium Dioxide 3.06 1.53
24. Triethyl citrate 2.52 1.26 25. Isopropyl alcohol q.s. q.s.
218.16 109.08
Stage V. Enteric Coating (Part II)
26. Seal coated pellets from stage II 70.56 35.28
27. Eudragit L100-55 5.1 2.55
28. Purified Talc 2.4 1.2
29. Titanium Dioxide 2.7 1.35
30. Triethyl citrate 1.08 0.54
31. Isopropyl alcohol q.s. q.s
81.84 40.92
Stage V . Capsule filling
32. Part i 218.16 109.08
33. Part II 81.84 40.92
34. Total fill wt. 300 150
35. Hydroxypropyl methylcellulose capsules
B. Manufacturing Procedure
Stage I: Drug core
a) Dissolve sucrose and sodium lauryl sulphate in sufficient water, further disperse in it. Dexlansoprazole and Magnesium oxide. Loading this dispersion over the sugar globules in FBC followed by drying at 50°c for 8 hours in drier.
Stage II: Seal coating
a) Dissolve HPMC 5cps and mannitol in sufficient water, further dispersed talc & titanium dioxide in it.
b) Take drug core pellets from stage I and apply seal coating with above suspension (a).
c) Dry the pellets at 50°c in drier.
Stage III: pH independent coating (Part IA)
a) Dissolve PVP K-30, Ethyl cellulose & triethyl citrate in sufficient isopropyl alcohol and dispersed titanium dioxide and talc in it.
b) With suspension prepared in (a), coat seal coated pellets from stage II.
c) Dry the pellets at 50°c in drier.
Step IV: Enteric coating (Part IB) a) Coat enteric coated pellets from stage III with following solution.
b) Dissolve Eudragit L100-55 and Triethyl citrate in Isopropyl alcohol sufficient quantity, further dispersed titanium dioxide and talc in it.
c) Dry the pellets at 50°c for in drier.
Stage V: Enteric coating (Part II):
a) Dissolve Eudragit L100-55 and Triethyl citrate in sufficient quantity of isopropyl alcohol, further dispersed talc & titanium talc in it.
b) Coat with above (a) suspension to seal coated pellets from stage II.
c) Dry the pellets at 50°c in drier.
Step VI: Pellets Filling
For filling into capsule mix both part I and Part II pellets. Fill into empty shell 150mg pellets for 30mg dose and 300mg pellets for 60mg dose.
[0086] Example No 4
A. Manufacturing formula
Quantity (mg/capsule)
Sr. No. Ingredients
60m g 30mg
Stagel. Drug core
1. Sugar Globules 121.5 60.75
2. Dexlansoprazole 60 30
3. Magnesium oxide 15.39 7.695
4. Sucrose 12.24 6.12
5. Sodium Lauryl Sulphate 12 6
6. Purified Water q.s. q.s.
221.13 110.565
Stagell. Seal Coating
7. Drug core pellets from Stage I 221.13 110.565
8. HPMC 5cps 21.63 10.815
9. Mannitol 10.8 5.4
10. Purified Talc 1.2 0.6
11. Titanium Dioxide 1.2 0.6
12. Purified Water q.s. q.s. 255.96 127.98
Stage III. pH independent coating (Part I A)
13. Seal coated pellets from Stage II 185.4 92.7
14. HPC 6.24 3.12
15. Purified Talc 3.06 1.53
16. Titanium Dioxide 3.06 1.53
17. Triethyl Citrate 2.52 1.26
18. Isopropyl Alcohol q.s. q.s.
200.28 100.14
Stage IV :- Enteric coating (Part IB)
19. Enteric coated pellets form stage III 200.28 100.14
20. Eudragit L100-55 9.24 4.62
21. Purified Talc 3.06 1.53
22. Titanium Dioxide 3.06 1.53
23. Triethyl citrate 2.52 1.26
24. Isopropyl alcohol q.s. q.s.
218.16 109.08
Stage V. Enteric Coating (Part II)
25. Seal coated pellets from stage II 70.56 35.28
26. Eudragit L100-55 5.1 2.55
27. Purified Talc 2.4 1.2
28. Titanium Dioxide 2.7 1.35
29. Triethyl citrate 1.08 0.54
30. Isopropyl alcohol q.s. q.s
81.84 40.92
Stage V . Capsule filling
31. Part i 218.16 109.08
32. Part II 81.84 40.92
33. Total fill wt. 300 150
34. Hydroxypropyl methylcellulose capsules B. Manufacturing Procedure
Stage I: Drug core
a) Dissolve sucrose and sodium lauryl sulphate in sufficient water, further disperse in it. Dexlansoprazole and Magnesium oxide. Loading this dispersion over the sugar globules in FBC followed by drying at 50°c for 8 hours in drier.
Stage II: Seal coating
a) Dissolve HPMC 5cps and mannitol in sufficient water, further dispersed talc & titanium dioxide in it.
b) Take drug core pellets from stage I and apply seal coating with above suspension (a).
c) Dry the pellets at 50°c in drier.
Stage III: pH independent coating (Part IA)
a) Dissolve HPC & triethyl citrate in sufficient isopropyl alcohol and dispersed titanium dioxide and talc in it.
b) With suspension prepared in (a), coat seal coated pellets from stage II.
c) Dry the pellets at 50°c in drier.
Step IV: Enteric coating (Part IB)
a) Coat enteric coated pellets from stage III with following solution.
b) Dissolve Eudragit L100-55 and Triethyl citrate in Isopropyl alcohol sufficient quantity, further dispersed titanium dioxide and talc in it.
c) Dry the pellets at 50°c for in drier.
Stage V: Enteric coating (Part II):
a) Dissolve Eudragit L100-55 and Triethyl citrate in sufficient quantity of isopropyl alcohol, further dispersed talc & titanium talc in it.
b) Coat with above (a) suspension to seal coated pellets from stage II.
c) Dry the pellets at 50°c in drier.
Step VI: Pellets Filling
For filling into capsule mix both part I and Part II pellets. Fill into empty shell 150mg pellets for 30mg dose and 300mg pellets for 60mg dose.

Claims

We Claim
1. A pharmaceutical composition comprising:
formulation (a) comprising: (i) a core particle comprising dexlansoprazole or a pharmaceutically acceptable salt or a hydrate thereof, and (ii) a pH-dependent release-controlled layer; and
formulation (b) comprising: (i) a core particle comprising dexlansoprazole or a pharmaceutically acceptable salt or a hydrate thereof, (ii) a pH-independent release-controlled layer, and (iii) a pH-dependent release-controlled layer.
2. The pharmaceutical composition according to claim 1, wherein composition is in a form of a capsule or a tablet.
3. The pharmaceutical composition according to claim 1, wherein the pH-dependent release-controlled layer of formulation (a) and (b) is soluble at a pH ranging from 4.5 to 6.0.
4. The pharmaceutical composition according to claim 1, wherein the pH-independent release-controlled layer of formulation (b) is soluble at a pH of 6.0 or above.
5. The pharmaceutical composition according to claim 1, wherein the core particle of formulation (a) and (b) is in a form of an active core particle comprising dexlansoprazole or a pharmaceutically acceptable salt or a hydrate thereof, or an inert core particle coated with a layer of dexlansoprazole or a pharmaceutically acceptable salt or a hydrate thereof.
6. The pharmaceutical composition according to claim 1, wherein the core particle of formulation (a) and (b) further contains a basic inorganic stabilizer.
7. The pharmaceutical composition according to claim 1, wherein the pH-independent release-controlled layer is formed of a hydrophilic polymer selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), carboxyvinyl polymer, polyethylene glycol 6000, lactose, mannitol, pullulan, agar, gellan gum, guar gum, carageenan, acacia gum, gum arabic, dextran, pectin and mixtures thereof.
8. The pharmaceutical composition according to claim 1, wherein the pH-independent release-controlled layer is formed of a hydrophobic polymer selected from the group consisting of ethyl cellulose, Eudragit® RL, Eudragit® RS, hydrogenated vegetable oils, glyceryl behenate, wax, fatty acid, fatty alcohol, shellac and mixtures thereof.
9. The pharmaceutical composition according to claim 1, wherein the pH-dependent release-controlled layer is formed of an enteric coating polymer selected from the group consisting of cellulose acetate trimellitate, methacrylic acid, methyl methacrylate copolymer, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl cellulose phthalate, hydroxypropyl ethyl cellulose phthalate, hydroxyl propyl methyl cellulose phthalate, hydroxyl propyl methyl cellulose acetate succinate, hydroxyethyl cellulose phthalate, methylcellulose phthalate, polyvinyl acetate phthalate, polyvinyl acetate hydrogen phthalate, amylase acetate phthalate, cellulose ester phthalates, cellulose ether phthalates, sodium cellulose acetate phthalate, starch acid phthalate, cellulose acetate butyrate, cellulose acetate maleate, cellulose acetate propionate, styrene maleic acid dibutyl phthalate copolymer, styrene maleic acid polyvinyl acetate phthalate copolymer propionate, shellac and mixtures thereof.
10. A pharmaceutical composition comprising: a pellet, a tablet, a granule, or a fine granule in which release of dexlansoprazole is controlled; wherein the pellet, tablet, granule, or the fine granule comprising:
a core particle comprising dexlansoprazole or a pharmaceutically acceptable salt or a hydrate thereof;
a pH-independent release-controlled layer on the core particle; and
a pH-dependent release-controlled layer on the pH-independent release-controlled layer.
11. The pharmaceutical composition according to claim 10, further comprising a seal coat layer on the core particle.
12. The pharmaceutical composition according to claim 10, wherein the pH-dependent release-controlled layer of the pellet, tablet, granule or fine granule in which the release of dexlansoprazole is controlled, is a layer soluble at a pH ranging from 4.5 to 6.
PCT/IB2016/054467 2015-07-28 2016-07-27 Novel dual delayed release oral composition of dexlansoprazole WO2017017615A1 (en)

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BR112018001539A BR112018001539A2 (en) 2015-07-28 2016-07-27 pharmaceutical composition
EP16829940.2A EP3328364A4 (en) 2015-07-28 2016-07-27 Novel dual delayed release oral composition of dexlansoprazole
CONC2018/0002046A CO2018002046A2 (en) 2015-07-28 2018-02-26 New oral delayed dual dexlansoprazole oral composition

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CN111991367A (en) * 2020-09-21 2020-11-27 青岛吉达巴尔国际贸易有限公司 Esomeprazole magnesium pulse pellet capsule and preparation method thereof
KR20220069270A (en) * 2020-11-20 2022-05-27 서울대학교산학협력단 pH-dependent tablet-in-capsule combination formulation containing dexransoprazole as an active ingredient and method for preparing the same

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Publication number Priority date Publication date Assignee Title
US20120058194A1 (en) * 2010-08-27 2012-03-08 Navin Vaya Pharmaceutical formulations comprising substituted benzimidazole derivatives

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WO2010117756A2 (en) * 2009-03-31 2010-10-14 Dr. Reddy's Laboratories Ltd Substituted benzimidazole pharmaceutical formulations
WO2013111149A1 (en) * 2011-12-21 2013-08-01 Hetero Research Foundation Controlled release solid oral compositions of dexlansoprazole

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Publication number Priority date Publication date Assignee Title
US20120058194A1 (en) * 2010-08-27 2012-03-08 Navin Vaya Pharmaceutical formulations comprising substituted benzimidazole derivatives

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111991367A (en) * 2020-09-21 2020-11-27 青岛吉达巴尔国际贸易有限公司 Esomeprazole magnesium pulse pellet capsule and preparation method thereof
KR20220069270A (en) * 2020-11-20 2022-05-27 서울대학교산학협력단 pH-dependent tablet-in-capsule combination formulation containing dexransoprazole as an active ingredient and method for preparing the same
KR102471545B1 (en) * 2020-11-20 2022-11-29 서울대학교 산학협력단 pH-dependent tablet-in-capsule combination formulation containing dexransoprazole as an active ingredient and method for preparing the same

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CO2018002046A2 (en) 2018-02-28
EP3328364A1 (en) 2018-06-06

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